by Jeffrey T. Kirchner, DO, AAHIVS, AAHIVM Chief Medical Officer

November 5, 2019

Featured Literature:

Braun DL et al. Noninferiority of simplified dolutegravir monotherapy compared to continued combination antiretroviral therapy that was initiated during primary HIV infection: A randomized, controlled, multisite, open-label noninferiority trial. Clin Infect Dis November 1, 2019; 69:1489-97.

Hocqueloux L et al. for the MONCAY study group. Dolutegravir monotherapy versus dolutegravir/abacavir/lamivudine for virologically suppressed people living with chronic HIV infection: The randomized noninferiority MONotherapy of TiviCay Trial. Clin Infect Dis November 1, 2019; 69:1498-1505.

Bart JA and Rokx C. Antiretroviral therapy for HIV: Game Over or Future Perspectives. Clin Infect Dis November 1, 2019; 69:1506-07.

Since dolutegravir (DTG) was first approved by the FDA in 2013, its pharmacologic characteristics including potency and high genetic barrier to resistance made it an attractive agent to study as monotherapy for persons with HIV. Unfortunately, this strategy failed in three early trials of patients with chronic HIV although drug resistance was uncommon. Two recently published studies have continued to look at DTG monotherapy. The first study (EARLY-SIMPLIFIED) from Switzerland included 101 patients who started ART < 180 days after documented primary HIV-1 infection and HIV-RNA level of <50 copies/mL for at least 48 weeks. The study simplified therapy for 68 patients to DTG monotherapy and 33 continued with combination ART. At week 48, ALL patients maintained undetectable viral loads, thus showing monotherapy with DTG was non-inferior to cART.

In the MONCAY study, 158 chronically HIV-infected patients with an HIV-RNA level of <50 copies for at least one year or longer while taking dolutegravir, lamivudine, and abacavir were randomized to continue this same three-drug therapy or change to DTG monotherapy. At 24 weeks, 73/78 (94%) of patients on DTG monotherapy and 77/80 (96%) of patients on cART had undetectable viral loads. During additional follow-up at 48 weeks, there were 10 virologic failures in the monotherapy arm and none in the cART group. Only two of the patients who failed DTG monotherapy had resistance mutations to INSTI. All DTG failures were transitioned to standard triple therapy.

Author’s Commentary:

I believe the data from the MONCAY study further puts to rest the utility of dolutegravir monotherapy. The accompanying editorial by Bart basically agrees, however notes the different patient populations in the monotherapy studies – suggesting that persons with chronic infection have larger HIV reservoirs with resultant reactivation of provirus containing INSTI resistance mutations which ultimately leads to virologic failure. Going forward, there appears to be no clinical reason to use monotherapy with our patients. Moreover, we have very good data supporting dual therapy without the use of NRTIs. Monotherapy trials, at least with DTG may be appropriate with strict entry including a short window of infection, close patient follow-up and as Bart points out – approval from an ethics committee.

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